NM_006031.6:c.6374A>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006031.6(PCNT):c.6374A>C(p.His2125Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0906 in 1,613,722 control chromosomes in the GnomAD database, including 12,050 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 4358 hom., cov: 32)

Exomes 𝑓: 0.082 ( 7692 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.706

Publications

18 publications found

Variant links:

Genes affected

PCNT (HGNC:16068): (pericentrin) The protein encoded by this gene binds to calmodulin and is expressed in the centrosome. It is an integral component of the pericentriolar material (PCM). The protein contains a series of coiled-coil domains and a highly conserved PCM targeting motif called the PACT domain near its C-terminus. The protein interacts with the microtubule nucleation component gamma-tubulin and is likely important to normal functioning of the centrosomes, cytoskeleton, and cell-cycle progression. Mutations in this gene cause Seckel syndrome-4 and microcephalic osteodysplastic primordial dwarfism type II. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PCNT Gene-Disease associations (from GenCC):

microcephalic osteodysplastic primordial dwarfism type II
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
Moyamoya disease
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

PCNT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.401539E-4).

BP6

Variant 21-46416292-A-C is Benign according to our data. Variant chr21-46416292-A-C is described in ClinVar as Benign. ClinVar VariationId is 138622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.6374A>C	p.His2125Pro	missense_variant	Exon 30 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.6020A>C	p.His2007Pro	missense_variant	Exon 30 of 47		NP_001302458.1	O95613-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 link	c.6374A>C	p.His2125Pro	missense_variant	Exon 30 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.176

AC:

26805

AN:

151950

Hom.:

4353

Cov.:

show subpopulations

Gnomad AFR

AF:

0.434

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0938

Gnomad ASJ

AF:

0.0864

Gnomad EAS

AF:

0.00559

Gnomad SAS

AF:

0.0914

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0762

Gnomad OTH

AF:

0.162

GnomAD2 exomes

AF:

0.0957

AC:

24068

AN:

251396

AF XY:

0.0904

show subpopulations

Gnomad AFR exome

AF:

0.444

Gnomad AMR exome

AF:

0.0551

Gnomad ASJ exome

AF:

0.0863

Gnomad EAS exome

AF:

0.00321

Gnomad FIN exome

AF:

0.108

Gnomad NFE exome

AF:

0.0747

Gnomad OTH exome

AF:

0.0822

GnomAD4 exome

AF:

0.0817

AC:

119349

AN:

1461654

Hom.:

7692

Cov.:

AF XY:

0.0808

AC XY:

58750

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.455

AC:

15235

AN:

33460

American (AMR)

AF:

0.0597

AC:

2670

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0849

AC:

2218

AN:

26136

East Asian (EAS)

AF:

0.00186

AC:

AN:

39700

South Asian (SAS)

AF:

0.0848

AC:

7315

AN:

86252

European-Finnish (FIN)

AF:

0.103

AC:

5525

AN:

53418

Middle Eastern (MID)

AF:

0.0735

AC:

424

AN:

5768

European-Non Finnish (NFE)

AF:

0.0720

AC:

80020

AN:

1111828

Other (OTH)

AF:

0.0972

AC:

5868

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

6302

12603

18905

25206

31508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3094

6188

9282

12376

15470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.177

AC:

26843

AN:

152068

Hom.:

4358

Cov.:

AF XY:

0.173

AC XY:

12868

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.433

AC:

17936

AN:

41402

American (AMR)

AF:

0.0935

AC:

1430

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0864

AC:

300

AN:

3472

East Asian (EAS)

AF:

0.00560

AC:

AN:

5180

South Asian (SAS)

AF:

0.0913

AC:

440

AN:

4820

European-Finnish (FIN)

AF:

0.107

AC:

1129

AN:

10600

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0761

AC:

5177

AN:

67988

Other (OTH)

AF:

0.166

AC:

349

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

926

1851

2777

3702

4628

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

244

488

732

976

1220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.120

Hom.:

1881

Bravo

AF:

0.187

TwinsUK

AF:

0.0642

AC:

238

ALSPAC

AF:

0.0724

AC:

279

ESP6500AA

AF:

0.433

AC:

1907

ESP6500EA

AF:

0.0758

AC:

652

ExAC

AF:

0.103

AC:

12569

Asia WGS

AF:

0.103

AC:

357

AN:

3478

EpiCase

AF:

0.0702

EpiControl

AF:

0.0705

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 26, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.5

(source)

DANN

Benign

0.27

DEOGEN2

Benign

0.015

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.17

MetaRNN

Benign

0.00064

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.9

PhyloP100

0.71

PrimateAI

Benign

0.28

PROVEAN

Benign

2.1

REVEL

Benign

0.060

Sift

Benign

1.0

Sift4G

Benign

0.84

Polyphen

0.0

Vest4

0.039

MPC

0.13

ClinPred

0.00087

GERP RS

3.5

Varity_R

0.042

gMVP

0.070

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over